Treatment of acute exacerbation of asthma and reduction of likelihood of hospitalization of patients suffering therefrom

ABSTRACT

The invention provides a method of improving one or more clinical outcomes of an individual experiencing an acute respiratory attack. The acute respiratory attack may include acute reversible bronchospasm, severe acute bronchospasm, or acute exacerbation of asthma. The method includes administering to an individual suffering from an acute respiratory attack an effective amount of bedoradrine or a pharmaceutically acceptable salt thereof in combination with a standard of care (SOC) treatment regimen.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application claims priority from U.S. Provisional Application Nos.61/262,352 and 61/392,917, filed Nov. 18, 2009 and Oct. 13, 2010,respectively, and incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to a method of treating severe episodes ofasthma, preventing the manifestations of severe and long-lastingepisodes of asthma from worsening, and reducing the likelihood ofhospitalization (or other adverse clinical outcomes) of patientssuffering from severe and long-lasting episodes of asthma, includingwithout limitation, acute exacerbation of asthma. In particular, thistherapeutic approach with MN-221 (generic name: bedoradrine) providesadditional bronchodilation and improved clinical outcomes includingreduced hospitalization when used adjunctively to (that is, incombination with) recognized standard respiratory care for acute asthmaexacerbations (i.e., nebulized albuterol, nebulized ipratropium,corticosteroids). This invention is particularly well-suited forpatients who fail to respond to this standard acute respiratory care orsimply “standard of care” treatment regimen.

BACKGROUND

Acute exacerbation of asthma (AEA) or status asthmaticus is along-lasting and severe asthma episode that is typically not responsiveto bronchodilator or corticosteroid therapy. An AEA may be diagnosed,for example and without limitation, by the symptoms of dyspnea andbronchospasm. Patients often experience progressively worseningbreathlessness, cough, wheezing, and chest tightness, or somecombination of these symptoms of AEA.

Current standard of care (SOC) for AEA treatment relies on using lowflow oxygen, inhaled β-agonists (e.g., albuterol), anticholinergics(ipratropium), and/or intravenous or oral corticosteroids (e.g.,prednisone and methylprednisolone); intravenous (IV) magnesium may beincluded. In some countries or at some points in time, IV orsubcutaneous (SC) adrenoceptor agonists (e.g., epinephrine in adults andterbutaline in children) and IV aminophylline may also be administered,but are not generally recommended at least for adults according to thecurrent NAEPP Asthma Guidelines (2007). See; also, S. C. Lazarus NEJMAug. 19, 2010; G. J. Browne et al. Lancet (1997) 349:301). Moreover,these treatments may not produce a significant clinical benefit and/ormay provoke unwanted cardiovascular side-effects (e.g., tachycardia)when added to SOC. Although subcutaneous adrenalin or terbutaline inconjunction with nebulized albuterol and corticosteroid andaminophylline were reported over 20 years ago (M. A. Spiteri et al.Thorax (1988) 43:19-23) to provide some breathing benefit without undueside effects, such parenteral beta-agonist therapy has proven over theyears to be too risky—especially from a cardiovascular liabilitystandpoint—for limited observed benefit.

Recently, D. S. Wheeler et al. Pediatr. Crit. Care Med. (2005) 6:142-7showed that terbutaline added to SOC in children with status asthmaticusdid not provide a significant improvement in clinical asthma score orICU stay. A reanalysis of data by G. J. Browne et al. Pediatr. Crit.Care Med. (2002) 3(2) led these authors to conclude that a single-doseintravenous salbutamol bolus in the initial treatment of children withacute severe asthma in the emergency department has the potential toshorten the duration of severe attacks and reduce overall requirementsfor inhaled salbutamol maintenance. However, a review conducted by A. H.Travers et al. Chest (2002) 122:1200-1207 of publications, whichdescribed randomized controlled trials comparing the use of IVβ₂-agonists versus placebo or SOC, led these authors to conclude that“[e]vidence is lacking to support the use of IV β₂-agonists in[emergency department] patients with severe acute asthma. Moreover, theclinical benefit appears questionable, while the potential clinicalrisks are obvious. The only recommendations for IV β₂-agonist use shouldbe in those patients in whom inhaled therapy is not feasible, or in thecontext of a controlled clinical trial comparing IV β₂-agonists withstandard care vs standard care alone.” Hence, there appears to be littleagreement in the literature as to the potential benefits of β-agonistsadministered intravenously. There may also be questions surrounding themerits of intravenous administration in children versus adults, who aresuffering from a acute severe asthma attack and present themselves in anemergency department setting.

Although the results of a study by Appel et al. J. Allergy Clin.Immunol. (1989) 84:90-98 do not clearly define the role of systemicβ-agonists in the treatment of life-threatening asthma, it suggests thatsubcutaneous administration of epinephrine or terbutaline should beconsidered in patients unresponsive to continuous nebulized β₂-agonists,and in those patients unable to cooperate due to alteration of mentalstatus or an inability to tolerate inhaled therapy. Epinephrine may alsobe delivered in intubated patients not responding to inhaled therapyduring mechanical ventilation. Subcutaneously, 0.3-0.5 mL (1:1000) ofepinephrine can be administered every 20 min. to a maximum of threedoses. Terbutaline can be administered subcutaneously (0.25-0.5 mg) andis the preferred treatment in pregnant females.

Intravenous infusion of terbutaline starting at 0.05-0.10 μg/kg per minhas been utilized predominantly in pediatric patients. It may beconsidered in the treatment of patients with no response to inhaled orsubcutaneous treatment, and in whom respiratory arrest is imminent, orin patients not adequately ventilated despite optimal setting of theventilator. A recent double blind, randomized controlled trial by Bogieet al. Pediatric Emergency Care (2007) 23(6) evaluated the benefit ofintravenous terbutaline in 49 nonventilated children with acute severeasthma who were already on continuous high-dose nebulized albuterol.Although the use of intravenous terbutaline was associated withimprovement in the clinical asthma severity score over the first 24 h,shorter use of continuous nebulized albuterol, and shorter ICU stay, thedifferences were not statistically significant.

The Applicants have identified novel methods for the treatment of severeasthma attacks, including AEA, especially in patients who fail torespond to current SOC. The Applicants have also discovered thatbronchodilation and the reduced hospitalization of patients sufferingfrom such attacks can be achieved by administering MN-221 orpharmaceutically acceptable salts thereof (collectively, Active Agent,as described further below). The discovery that Active Agent isparticularly beneficial in treating patients suffering from an acutesevere respiratory attack could not have been predicted from theclinical experience of those of ordinary skill in the art using knownbeta-agonists. Moreover, the Applicants' believe that their discoverieshave special utility in treating an “exacerbation-prone” subset ofasthmatics, who are at a higher risk of experiencing an acuteexacerbation of asthma (for a discussion of this subset of asthmaticssee, R. H. Dougherty Clin. Exp. Allergy. (2009) 39:193).

SUMMARY OF THE INVENTION

Provided herein are methods for pharmacologically treating severe andlong-lasting episodes of asthma, by providing intravenous administrationof a highly β₂-selective adrenoceptor agonist in conjunction with astandard of care treatment regimen and thus preventing themanifestations of severe and long-lasting episodes of asthma fromworsening, and reducing the likelihood of hospitalization of patientssuffering from severe and long-lasting episodes of asthma, includingwithout limitation, acute exacerbation of asthma. Also provided hereinare methods for selecting patients that are likely or unlikely toundergo such treatment.

In one aspect, the present invention provides a method of treating AEA,comprising administering an effective amount of the Active Agent to apatient in need of such treatment. In certain other aspects andembodiments, the invention also provides novel methods of reducing thelikelihood of hospitalization (e.g., a reduced hospitalization rate or areduced stay in an intensive care unit) and/or worsening of one or moremanifestations of AEA in a patient suffering from AEA comprisingadministering an effective amount of the Active Agent to such patient.In other aspects, other methods of the present invention comprisedetermining that a patient is suffering from a long-lasting and severeasthma episode that is not responsive to initial standard of caretreatment and administering to the patient an effective amount of theActive Agent. In a preferred embodiment, the Active Agent isadministered parenterally, more preferably, intravenously.

The Active Agent (MN-221 a/k/a bedoradrine or its pharmaceuticallyacceptable salts) administered intravenously allows it to distribute andpartition into the congested lung tissue of AEA patients and allowbronchodilation without undue cardiovascular side effects. Table 1,below, provides an example of the adrenoceptor action profile for MN-221determined experimentally:

TABLE 1 Adrenoceptor Action Profile for MN-221 μM Study System β1 β2β1/β2 Comment Cerep Competitive   11.8 0.27 42 HEK (Human β1), 14320Binding (IC₅₀) CHO (Hu β2) cell bioassay >50  0.013 >3000 HEK (Humanβ1), (EC50 cAMP CHO (Hu β2) accum.) Cerep ex vivo Organ ~1* 0.028 36 GPRt atrium (% 13271 bioassay (est isoprot); EC39*, EC50) GP carbachol-txtrachea (% salbut) a partial agonist. Emax = 39% *= EC₃₉ i.e., 39% ofisoproterenol maximum response

In another aspect, the present invention provides a method of treatingAEA by administering an effective amount of the Active Agent to apatient in need of such treatment wherein the AEA or one or moremanifestations of the AEA are non-responsive or substantiallynon-responsive to treatment with SOC. In another aspect, the presentinvention provides a method of treating a severe and long-lastingepisode of asthma by administering an effective amount of the ActiveAgent to a patient in need of such treatment, wherein the severe andlong-lasting episode of asthma or one or more manifestations of it arenon-responsive or substantially non-responsive to treatment with SOC.Within the aspects and embodiments of the present invention, in oneembodiment, the Active Agent administered is MN-221 or pharmaceuticallyacceptable salts thereof. For example and without limitation, patientssuffering from AEA (for example, those admitted to an emergency roombecause of an acute exacerbation of asthma), who were not responsive toSOC, were treated with MN-221 (in addition to having been treated withSOC) and their treatment outcomes compared with those of similarpatients treated with SOC only (or SOC plus a placebo). Thehospitalization rate among those patients who were treated with SOConly, was 54 percent (7 of 13, roughly half), compared to ahospitalization rate of 25 percent (4 of 16, roughly a quarter) amongthose patients who were treated with MN-221 and with SOC, demonstratingimproved breathing ability (see, FIG. 1) and about a 50 percentreduction in hospitalization rate among AEA patients who were alsotreated with MN-221. Thus, the invention also provides novel methods ofreducing the likelihood of hospitalization of patients suffering fromAEA, who are non-responsive to SOC. In one embodiment of the invention,the likelihood of hospitalization of a patient suffering from an acuteexacerbation of asthma treated with MN-221 alone or in combination withSOC falls to substantially less than half or fifty percent, preferably,to about a quarter (or twenty-five percent) of all patients sufferingfrom an acute respiratory attack.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the improvement over baseline of FEV₁ between patientsbeing treated with placebo and SOC versus patients being treated with acombination of SOC and MN-221.

FIG. 2 shows the absence of an adverse change in heart rate for patientsreceiving placebo and SOC versus patients receiving a combination ofMN-221 and SOC.

FIG. 3 depicts the heart rate of dogs receiving vehicle, albuterol andthree dosage levels of MN-221 adjunctive to albuterol.

A DESCRIPTION OF PREFERRED EMBODIMENTS

The invention provides a method of improving one or more clinicaloutcomes of an individual experiencing an acute respiratory attack. Theacute respiratory attack is severe and usually requires that theindividual present himself or herself to an emergency department (i.e.,emergency room) of a hospital. An acute respiratory attack may includean acute reversible bronchospasm, a severe acute bronchospasm, or anacute exacerbation of asthma. The inventive method comprisesadministering to an individual suffering from an acute respiratoryattack an effective amount of bedoradrine or a pharmaceuticallyacceptable salt thereof in combination with a standard of care (SOC)treatment regimen. The bedoradrine or a pharmaceutically acceptable saltthereof can be administered after administration of the SOC treatmentregimen, contemporaneously with the SOC treatment regimen, or beforeadministration of the SOC treatment regimen. A SOC treatment regimencomprises administration of one or more β-agonist bronchodilators, oneor more anti-cholinergic drugs, one or more corticosteroids, orcombinations thereof. The SOC treatment regimen may also includes theadministration of magnesium.

Typically, the one or more β-agonist bronchodilators, or one or moreanti-cholinergic drugs are administered by inhalation, injection, orintravenous infusion. The one or more β-agonist bronchodilators may beselected from albuterol, bitolterol, levalbuterol, pirbuterol,epinephrine, terbutaline, formoterol, or salmeterol, whereas the one ormore anti-cholinergic drugs may, in turn, be selected from ipratropiumor tiotropium. The one or more corticosteroids may be selected fromprednisone, methylprednisolone, or prednisolone.

The bedoradrine or a pharmaceutically acceptable salt thereof may beadministered by any suitable route, but more preferably, intravenously,orally, or by inhalation. The amount of bedoradrine or apharmaceutically acceptable salt thereof administered to an individualtypically falls in the range of 100 to 5,000 μg. More preferably, about500 to about 1,500 μg of bedoradrine or a pharmaceutically acceptablesalt thereof is administered intravenously over a period of about 5 toabout 120 minutes. The invention provides for one or more improvedclinical outcomes. Such improved clinical outcomes may include anincrease in FEV₁, a reduction in likelihood of hospitalization, animprovement in dyspnea scores, a reduction in incidence of intubation, areduction in length of stay in an intensive care unit and an improvementin self-ambulation unaccompanied by respiratory distress. Usually, theFEV₁ improves by 5% or more, 10% or more, or 15% or more.

The Applicants have found that the likelihood of hospitalization of anindividual receiving the claimed combination (i.e., MN-221 plus SOC)treatment is reduced compared with an individual receiving only the SOCtreatment regimen. (Whenever the term “placebo” is mentioned in thisdisclosure in combination with SOC, what it is meant is that anindividual simply continues to receive the SOC treatment regimen and notest drug, such as MN-221 or a pharmaceutically acceptable saltthereof.) Following the teachings of the invention, the likelihood ofhospitalization of an individual receiving the claimed combinationtreatment is reduced to about 25% or less, about 20% or less, or about15% or less. An individual who will tend to benefit from theadministration of bedoradrine or its pharmaceutically acceptable salt isan individual who is not responsive to an inhaled β-agonistbronchodilator, most typically albuterol. Such an individual is likelyto experience an improvement from the acute respiratory attack for about1 hour or more, about 2 hours or more, about 3 hours or more, about 4hours or more, about 5 hours or more, about 6 hours or more, or about 8hours or more after the claimed combination treatment. The nature of theimprovement may typically manifest itself in the form of an improvementin FEV₁ (L), FEV₁ (% predicted), PEFR, arterial blood oxygen saturation,respiratory rate, or combinations thereof after the claimed combinationtreatment, unaccompanied by one or more clinically observable adverseevents. Such clinically observable adverse events may include, but arenot limited to, an increased heart rate, an increased blood glucose,tremor, headache, palpitations, or a jittery feeling.

The invention is also directed to a method of alleviating one or morenegative effects of an acute respiratory attack selected from the groupconsisting of acute reversible bronchospasm, severe acute bronchospasmand acute exacerbation of asthma, comprising administering to a patient,who has been diagnosed as suffering from either acute reversiblebronchospasm, severe acute bronchospasm, or acute exacerbation ofasthma, an effective amount of bedoradrine or a pharmaceuticallyacceptable salt thereof. More specifically, the patient suffers from anacute, severe asthma attack, otherwise known as an acute exacerbation ofasthma. Target patients of the invention will be those who typicallyfail to respond to an SOC treatment regimen. In the Applicants' hands,such a patient experiences improved FEV₁ relative to the patient'spre-treatment FEV₁ and the improved FEV₁ persists on average for atleast about 6 hours at a level that is about 50% or more of a peakeffect. A preferred daily amount of bedoradrine or a pharmaceuticallyacceptable salt thereof administered to a patient falls in the range ofabout 300 to 1500 μg. Applicants believe that the invention will find aspecial utility in treating persons who belong to an exacerbation-pronesubset of asthmatics, who are typically at high risk of suffering froman acute exacerbation of asthma.

Other preferred embodiments of this invention will become evident from adetailed study of this disclosure. Applicants' wish to incorporate byreference herein the entirety of the disclosures of any patent ornon-patent reference cited anywhere in this disclosure.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following definitions are provided to assist the reader. Unlessotherwise defined, all terms of art, notations and other scientific ormedical terms or terminology used herein are intended to have themeanings commonly understood by those of skill in the chemical andmedical arts. In some cases, terms with commonly understood meanings aredefined herein for clarity and/or for ready reference, and the inclusionof such definitions herein should not necessarily be construed torepresent a substantial difference over the definition of the term asgenerally understood in the art.

“Active Agent” refers to an agent selected from the group consisting ofMN-221, the free base form of MN-221, other pharmaceutically acceptablesalts of the MN-221 free base (e.g., organic or inorganic acid additionsalts), their pharmaceutically acceptable metabolites (e.g., acarboxylic acid), and pharmaceutically acceptable salts of theirmetabolites.

“Administering” or “Administration of” a drug to a patient (andgrammatical equivalents of this phrase) includes both directadministration, including self-administration, and indirectadministration, including the act of prescribing a drug. For example, asused herein, a physician who instructs a patient to self-administer adrug and/or provides a patient with a prescription for a drug isadministering the drug to the patient.

“Effective amount” of a drug is an amount of a drug that, whenadministered to a patient with AEA, will have the intended therapeuticeffect, e.g., alleviation, amelioration, palliation or elimination ofone or more manifestations of AEA in the patient. The full therapeuticeffect does not necessarily occur by administration of one dose (ordosage), and may occur only after administration of a series of doses.Thus, a therapeutically effective amount may be administered in one ormore administrations.

“First line treatment” refers to a treatment intended as an initialtreatment of AEA. When first line treatment fails or is inadequate,subsequent treatments referred to as second line treatment and thirdline treatment may be used.

“Manifestation” of AEA refers to a symptom, sign, physiological state(e.g., heart rate, cough, shortness of breath and/or difficulty ofbreathing, hypoxia, or anxiety associated with inability to breathe), orreport (e.g., FEV₁, FEV₁%, or PEER) characteristic of a patient withAEA.

“MN-221” refers to the sulfate salt of formula: acetamide,N,N-dimethyl-2-[[(7S)-5,6,7,8-tetrahydro-7-[[(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)phenyl]ethyl]amino]-2-naphthalenyl]oxy],sulfate (also known asbis[2-[[(7S)-7-[[(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)phenyl]ethyl]amino]-5,6,7,8-tetrahydronaphthalen-2-yl]oxy]-N,N-dimethylacetamide]sulfate or(−)-bis(2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)phenyl]ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethyl-acetamide)monosulfate).

MN-221 is synthesized according to methods reported in literature. See,e.g., the references Yanagi et al. Chem. Pharm. Bull. (Tokyo) (2003)51(2):221-23 and U.S. Pat. No. 6,133,266. Without being bound bymechanism, MN-221 may possess a greater selectivity for the human β₂receptors than β-agonists commonly used to treat acute exacerbation ofasthma (i.e., albuterol, levalbuterol, terbutaline). In addition, MN-221may act as a full agonist at β₂-adrenergic receptors and a partialagonist at the β₁-adrenergic receptor. The MN-221 may providebronchodilation with a reduced risk of cardiovascular complications(e.g., tachycardia, arrhythmia). An example of a pharmaceuticallyacceptable metabolite of MN-221 includes, without limitation, ametabolite resulting from the hydrolysis of the amide moiety. Acarboxylic acid, representative of a hydrolysis product, is described inU.S. Pat. No. 6,136,852, the disclosure of which is incorporated hereinby reference.

“Patient,” “individual,” or “subject” refers to humans.

“Reduction” of a symptom or symptoms (and grammatical equivalents ofthis phrase) means decreasing of the severity or frequency of thesymptom(s), or elimination of the symptom(s). A reduction in alikelihood of hospitalization means a lowering of a frequency ofhospitalization or a reduction in a hospitalization rate, for example,from a 50% rate to a 25% rate, or lower, such as 15% or 10%.

“Treating” a condition or patient refers to taking steps to obtainbeneficial or desired results, including clinical results. For purposesof the various aspects and embodiments of the present invention,beneficial or desired clinical results include, but are not limited to,reduction, alleviation or amelioration of one or more manifestations ofor negative effects of an acute respiratory attack (e.g., AEA),improvement in one or more clinical outcomes, diminishment of extent ofdisease, delay or slowing of disease progression, amelioration,palliation or stabilization of the disease state, and other beneficialresults described herein.

Various aspects and embodiments of the invention are describedhereinafter. It should be noted that the specific embodiments are notintended as an exhaustive description of the invention or as alimitation on the scope of the invention. One aspect or embodiment,described in conjunction with a particular embodiment of the presentinvention is not necessarily limited to that embodiment and can bepracticed with any other embodiment(s) of the invention.

In one aspect, the present invention provides a method of treating AEA,comprising administering an effective amount of the Active Agent to apatient in need of such treatment. In certain other aspects andembodiments, the invention also provides novel methods of preventinghospitalization, or reducing a rate of hospitalization and/or worseningof one or more manifestations of AEA in a patient suffering from AEAcomprising administering an effective amount of the Active Agent to thepatient in need of such prevention. In other aspects, other methods ofthe present invention comprise determining that a patient is sufferingfrom a long-lasting and severe asthma episode that is not responsive toinitial standard of care treatment and administering to thenon-responsive patient an effective amount of the Active Agent.

In another aspect, the present invention provides a method of treatingAEA by administering an effective amount of the Active Agent to apatient in need of such treatment wherein the AEA or one or moremanifestations of the AEA are non-responsive or substantiallynon-responsive to treatment with SOC. One of skill in the art, uponreading this disclosure will be able to determine, based on theseverity, improvement, and worsening of the manifestations of AEA,whether a patient is substantially or completely unresponsive totreatment with SOC. In another aspect, the present invention provides amethod of treating a severe and long-lasting episode of asthma byadministering an effective amount of the Active Agent to a patient inneed of such treatment, wherein the severe and long-lasting episode ofasthma or one or more manifestations of it are non-responsive orsubstantially non-responsive to treatment with SOC.

In another aspect, the present invention provides methods of preventinghospitalization, or reducing the likelihood of hospitalization, of apatient suffering from an AEA, comprising administering to a patient,who has been diagnosed as suffering from AEA, an effective amount of theActive Agent. In one embodiment, the patient is suffering from along-lasting and severe asthma episode that is not responsive to initialbronchodilator, or corticosteroid, or combination therapy thereof. Thelong-lasting and severe asthma episodes include but is not limited topersistent cough secondary to asthma, shortness of breath and/ordifficulty of breathing secondary to asthma, hypoxia secondary toasthma, or anxiety associated with inability to breathe or shortness ofbreath that is not responsive to initial bronchodilator orcorticosteroid or combination therapy thereof.

Within the various aspects and embodiments of the present inventionprovided herein, in one embodiment, the Active Agent administered isMN-221.

In related embodiments, the patient treated shows as a symptom of AEA, adecreases in respiratory rate. In yet another embodiment, the patienthas been admitted to an emergency room. In other related embodiments,only about 20% to about 30% and only about 40% to about 50% of thepatients treated with the Active Agent are hospitalized. In yet anotherembodiment, the patient in accordance to the present invention refers topatent that is not responsive to albuterol or methylprednisolonetherapy, alone or in combination with one another.

In yet another embodiment, the present invention provides methods ofimproving FEV₁, FEV₁%, peak expiratory flow rate (PEFR) or arterialblood oxygen saturation of a patient suffering from AEA, comprising:administering to the patient an effective amount of the Active Agent.FEV₁ refers to the amount of air which can be forcibly exhaled from thelungs in the first second of a forced exhalation, and may be measured byspirometry. FEV₁% refers to FEV₁ expressed as a percentage of the vitalcapacity, and is an index for assessing and quantifying airflowlimitations. Vital capacity refers to the volume change of the lungbetween a full inspiration and a maximal expiration. In a relatedembodiment, the present invention provides methods of improving FEV₁,FEV₁%, PEFR, or arterial blood oxygen saturation, or decreasing arespiratory rate, of a patient suffering from AEA, comprisingadministering to a patient, who has been diagnosed as suffering fromAEA, an effective amount of the Active Agent. Typically, an improvementin FEV₁ or FEV₁% or PEFR or arterial blood oxygen saturation, or adecrease in respiratory rate, is achieved without observing clinicallymeaningful changes in heart rate, systolic, or diastolic blood pressure,or serum potassium when such administration is coupled to other standardof care treatments for acute exacerbation of asthma.

In another embodiment, the improved FEV₁ is determined in comparisonwith a pre-treatment FEV₁. In another embodiment, the improved FEV₁persists on average for at least about 5 hours at a level that is about50% or more of a peak effect. The term “peak effect,” as used herein,refers to the highest, post-treatment percentage improvement in averageFEV₁. In another embodiment, the improved FEV₁ persists for about 2hours to about 12 hours, about 4 hours to about 10 hours, and for about6 hours to about 8 hours, at a level that is about 50%, about 60%, about70%, or more of the maximum average FEV₁ increase observed afterinitiating administration of the Active Agent.

An example of improved FEV₁ of patients suffering from an acuteexacerbation of asthma attack who were treated with a combination ofMN-221 and SOC is graphically shown in FIG. 1. The graphicalrepresentation also includes changes from baseline FEV₁ in patientsreceiving only SOC (that is, “Placebo+SOC,” which means patientsreceived continuous SOC only; “MN-221+SOC” means patients received acombination of MN-221 and SOC). The data is tabulated in Table 2.

TABLE 2 Percent Change in FEV₁ Liters at Hour 5 from Start of Infusion(Population: Intent-to-Treat) Change in At 5 Hours after Baseline Litersstart of Placebo + SOC 1.15 0.26 1.41 MN-221 + SOC 1.22 0.46 1.68

As noted above, when MN-221 was combined with standard of care inpatients with acute exacerbations of asthma, an observed clinicalbenefit was reduced hospitalization. Moreover, additionalbronchodilation was observed as measured by FEV₁ as depicted in Table 2.The placebo plus SOC group (that is, the continuous SOC group)experienced a 23% positive change in FEV₁ value. The MN-221 plus SOCgroup experienced a 38% positive change in FEV₁ value, however. The meanFEV₁ (L) change from baseline was 200 mL (0.20 L) greater in theMN-221+SOC dose group versus the Placebo+SOC dose group. This additionalbronchodilation benefit in the MN-221 dose group is depicted graphicallyin FIG. 1.

Importantly, the observed clinical benefits (e.g., reduction inhospitalization rate, additional bronchodilation, etc.) occurred in theabsence of significant heart rate increase, thus supporting safety andproviding unexpected results over the use of other β-agonists. Theabsence of a significant change in hear rate is depicted in FIG. 2.

In another aspect, the present invention provides a method of treating apatient suffering from an acute exacerbation of asthma comprisingadministering an effective amount of a pharmaceutical compositioncomprising a solution of MN-221 or a solution of a pharmaceuticallyacceptable salt of MN-221 thereby treating the patient. In anotherembodiment, the patient experiences an improved FEV₁, compared to apre-treatment FEV₁. In another embodiment, the improved FEV₁ persists onaverage for at least about 5 hours at a level that is about 50% or moreof a peak effect. In another embodiment, the improved FEV₁ persists forabout 2 hours to about 12 hours, about 4 hours to about 10 hours, andfor about 6 hours to about 8 hours, at a level that is about 50%, about60%, about 70%, or more of the maximum average FEV₁ increase observedafter initiating administration of the pharmaceutical composition.

In a preferred embodiment, the Active Agent is administered incombination with administration of SOC. Thus, the Active Agents isadministered to an AEA patient in combination with other agents orprocedures intended to treat AEA, ameliorate symptoms of AEA, potentiatethe effects of the Active Agents, or provide other therapeutic benefit.Administration of an agent “in combination with” includes paralleladministration (administration of both the agents to the patient over aperiod-of time), co-administration (in which the agents are administeredat approximately the same time, e.g., within about a few minutes to afew hours of one another, such as, administration of MN-221, andalbuterol, ipratropium, and/or prednisone or prednisolone on same days),and co-formulation (in which the agents are combined or compounded intoa single dosage form suitable for oral, inhaled or parenteraladministration).

In other embodiments, the SOC thus administered in combination comprisesone or more of a β-agonist, anti-cholinergic agent, and acorticosteroid. In another embodiment, the β-agonist is an inhaledβ-agonist. In another embodiment, the β-agonist is albuterol. In anotherembodiment, the albuterol is administered at a rate of from about 5mg/hr to about 5 mg once every 20 minutes. In another embodiment, thealbuterol administration is intermittent or continuous. In anotherembodiment, the anticholinergic agent is ipratropium. In yet anotherembodiment, the β-agonist or the anticholinergic agent is administeredemploying a nebulizer or an MDI (metered dose inhaler). In anotherembodiment, the corticosteroid is prednisone or methylprednisolone. Inanother embodiment, the corticosteroid is administered orally orparenterally.

In another aspect, the present invention provides a method of treating apatient suffering from an acute exacerbation of asthma comprisingadministering an effective amount of a pharmaceutical compositioncomprising a solution of MN-221 or a solution of a pharmaceuticallyacceptable salt of MN-221 and administering an effective amount of aninhalable pharmaceutical composition comprising a beta-agonist otherthan MN-221 or a pharmaceutically acceptable salt of the beta-agonist,thereby treating the patient. In another embodiment, the beta-agonistother than MN-221 is albuterol.

In another embodiment, the solution of MN-221 is administeredintravenously. In another embodiment, the MN-221 is administered in adaily amount of about 600 μg to about 1200 μg. In another embodiment,the effective amount of the pharmaceutical composition comprising asolution of MN-221 or a solution of a pharmaceutically acceptable saltof MN-221 is administered over a period of about 15 minutes to about 2hours.

In another aspect, the present invention provides a method of treating apatient suffering from an acute exacerbation of asthma comprising:

(a) administering an agent or a therapy that is a standard of care(SOC);

(b) determining if the patient exhibits a positive or negative responseto said step (a);

(c) discharging the patient if the patient exhibits a positive responseto said step (a);

(d) administering an effective amount of an injectable pharmaceuticalcomposition comprising a solution of MN-221 or a solution of apharmaceutically acceptable salt thereof, if the patient exhibits anegative response to said step (a);

(e) determining if the patient exhibits a positive or negative responseto said step (d);

(f) discharging the patient if the patient exhibits a positive responseto said step (d); and

(g) admitting the patient to a hospital if the patient exhibits anegative response to said step (d). In another embodiment, the patientdischarged in step (f) remains symptom-free on average for at leastabout 3 hours after discharge. In another embodiment, the patientdischarged in step (f) remains symptom-free on average for at leastabout 5 hours after discharge.

A potential scenario for admission, diagnosis and treatment of a patientsuffering from an acute respiratory attack is depicted in the flowdiagram, shown in Scheme 1 below, which is meant merely to beillustrative. (See, Lazarus, S. C., in N. Engl. J. Med. (2010)363:755-764.)

FEV1 denotes forced expiry volume in 1 second, ICU, intensive care unit,PaCO₂, partial pressure of arterial oxygen pressure, PaO₂, partialpressure of arterial oxygen, PFE, peak expiratory flow, and SaO₂,arterial oxygen saturation.

In other embodiments, the treatment methods provided herein are part ofa first line treatment. In other embodiments, the treatment methodsprovided herein are part of a second line treatment or part of a thirdline treatment.

In another aspect, the present invention provides a method of selectinga patient suffering from acute exacerbation of asthma as likely orunlikely to be suitable for treatment comprising administration ofMN-221 or a pharmaceutically acceptable salt thereof, the methodcomprising:

administering to the patient a standard of care (SOC), and

determining the FEV₁ of the patient,

wherein, if the FEV₁ is ≦about 55% of the predicted value, the patientis likely to undergo treatment comprising the administration of MN-221or a pharmaceutically acceptable salt thereof, andif the FEV₁ is >55% of the predicted value, the patient is unlikely toundergo treatment comprising the administration of MN-221 or apharmaceutically acceptable salt thereof, thereby selecting the patient.

In certain embodiments, if the FEV₁ is ≦about 50%, ≦about 40%, ≦about25% of the predicted value, the patient is likely to undergo treatmentcomprising the administration of MN-221 or a pharmaceutically acceptablesalt thereof.

As used herein, the “predicted value” of FEV₁ is a measure of FEV₁ whichmay be calculated following well known methods based on age, height,gender and race, and observed FVC, FEV₁, and FEF25-75% values. As usedherein, FVC refers to forced vital capacity, which is the total volumeof air that can be exhaled from the lungs during a forced expirationfollowing a maximal inspiration. As used herein, FEF25-75% refers toforced expiratory flow 25-75%, which is the average expired flow overthe middle half of the FVC maneuver and may be considered a sensitivemeasure of small airways narrowing.

In another embodiment, the patient is likely to be suitable fortreatment comprising administration of MN-221 or a pharmaceuticallyacceptable salt thereof. In another embodiment, the method furthercomprising administering to the patient an effective amount of apharmaceutical composition comprising a solution of MN-221 or a solutionof a pharmaceutically acceptable salt of MN-221, thereby treating theacute exacerbation of asthma. In another embodiment, the MN-221 isadministered in an amount of about 600 μg/patient to about 1200μg/patient. In another embodiment, the effective amount of thepharmaceutical composition is administered over a period of about 15minutes to about 2 hours. In another embodiment, the beta-agonist otherthan MN-221 is albuterol.

In certain embodiments, the patient may be selected from the followingpool of potential patient for practicing the methods of the presentinvention: they may be male or female; may have self-reported history ofphysician-diagnosed and treated asthma for ≧3 months; and may have adiagnosis of an acute exacerbation of asthma upon presentation at the EDas defined by dyspnea, evidence of bronchospasm, and by a known historyof asthma. Upon presentation to the ED, such patients may haveundergone: a brief physical examination that includes checking vitalsigns and auscultation, and assessing accessory respiratory muscle usageand the level of dyspnea the patient is experiencing; spirometry tomeasure the patient's FEV₁ (expressed as % of predicted); administrationof supplemental oxygen to maintain oxygen saturation as measured bypulse oximetry of ≧90%; administration of two doses of inhaledbeta2-agonist (e.g., and without limitation, about 5 mg of albuterol)via nebulizer (each dose given sequentially once a hour or about onceevery 20 minutes), simultaneously with two doses of an inhaledanti-cholinergic agent (e.g., and without limitation, 0.5 mgipratropium) via nebulizer (each dose given sequentially once aboutevery 20 minutes) and a dose of corticosteroid of about 60 mg givenorally (prednisone) or intravenously (methylprednisolone). The numberand amount of SOC administered may be altered as will be apparent to oneskilled in the art. The suitable patient may also have an FEV₁ ≧55%within about 10 minutes of completing the SOC treatment as describedimmediately above; have ECG with no dysrhythmias (except sinustachycardia); and have no clinical or electrocardiographic signs ofischemic heart disease.

The SOC administered as part of selecting patients and as part oftreating patients, in accordance to the present invention, may includestandardized care consistent with the National Asthma Education andPrevention Program (NAEPP) guidelines. Upon presentation to the ED forassessment and treatment for an acute exacerbation of asthma, thepatient may receive standardized care consistent with the NationalAsthma Education and Prevention Program (NAEPP) guidelines. Once thepatient has received the standardized initial treatment regimen and hasbeen assessed for response to that treatment (signs and symptoms ofacute asthma exacerbation), one or more of a 12-lead ECG, a dyspneaindex scale assessment, and spirometry may be performed. If thepatient's FEV₁ is ≦55% of predicted the patient may be suitable fortreatment in accordance with the present methods. Throughout thescreening process, the patient may continue to receive the appropriatemedical care consistent with the NAEPP guidelines for the intendedtreatment of acute exacerbations of asthma.

In certain embodiments, during the treatment period, the patient maycontinue to receive one or more of the following standard treatments andassessments until the patient's FEV₁ reaches ≧about 70%, of predicted.Such standard treatments and assessments include: assessment of thepatient's signs and symptoms; completion of a dyspnea index scale;supplemental oxygen to maintain oxygen saturation as measured by pulseoximetry of ≧about 90%; albuterol (2.5 mg) via nebulizer given hourly oronce every 20 minutes; ipratropium (0.5 mg) via nebulizer may be givenevery hour; spirometry completed within 10 minutes of nebulizertreatments; followed by, reassessment of signs and symptoms.

In certain embodiments, if the patient does not improve to FEV₁ ≧70% ofpredicted during the treatment period, the patient may continue toreceive further treatment including hospital admission. Safety, efficacyand PK parameters may be monitored throughout the treatment period. Aninitial 24-hour follow-up visit may be completed to evaluate thepatient's health status as well as for safety and PK parameters. Asecond follow-up contact may be completed by telephone seven dayspost-randomization for safety purposes and to evaluate the patient'shealth status. The occurrence of clinical signs, symptoms, laboratoryabnormalities, ECG abnormalities suggesting toxicity, or results ofefficacy analyses (FEV₁, dyspnea index scale), may result in a decisionto modify the proposed planned dose escalations, to repeat a dose level,or to not evaluate any additional dose(s) of MN-221.

One or more of the following outcomes may be used to determine theusefulness of the present methods. They include: a change of FEV₁expressed as percent of predicted after two doses of albuterol (e.g.,and without limitation at about 2.5 mg to about 5 mg each) andipratropium (e.g., and without limitation at about 0.5 mg each) whencompared to FEV₁ 2 hour after (“hour 2”) the start of MN-221 infusion;the safety, tolerability, and pharmacokinetic profile of MN-221 whenadministered after two doses of albuterol (e.g., and without limitationat about 5 mg each) and ipratropium (e.g., and without limitation atabout 0.5 mg each) in patients with acute exacerbation of asthma; ameasurement of FEV₁% of predicted at time points other than about hour 2(e.g., and without limitation at about hour 3, about hour 4, about hour5, about hour 6, about hour 7, and about hour 8); a measurement of FEV₁(L); a measurement of PEFR (L/sec); a measurement of PEFR, expressed aspercent (%) of predicted; and a measurement of dyspnea index scale. Asused herein, e.g., “hour 2” refers to 2 hours after administration ofMN-221, and includes 2 hours after stopping administration of MN-221.The various aforementioned outcomes may be measured at time intervals ofabout hours 1, 2, 3, 4, 5, 6, 7, 8, and 24; additionally the dyspneaindex scale may be measured at about day 8 also. One or more of thefollowing outcomes may also be used to determine the usefulness of thepresent methods: a measurement of the number of albuterol treatments incombination with MN-221 to achieve FEV₁ ≧50%, ≧60%, and ≧70%; ameasurement of time to achieve FEV1 ≧50%, 60%, and ≧70%; a measurementof the hospital admission rate; a measurement of the length of stay inhospital (in hours); and a measurement of the intensive care unit (ICU)admission rate.

In another embodiment, the standard of care comprises one or more ofabout 2.5 mg to about 5 mg of albuterol administered by a nebulizer, orMDI about 1 mg of ipratropium administered by a nebulizer, or MDI; about50 mg of prednisone administered orally, or about 50 mg ofmethylprednisolone administered intravenously; and about 2 gm ofmagnesium sulfate administered intravenously.

In certain other embodiments within the various aspects and embodimentsof the present invention, the Active Agent is administered i.v. in adaily amount of about 2400 μg (or 2.4 mg), about 1200 μg, about 1000 μg,about 800 μg, about 600 μg, about 450 μg, about 250 μg. In otherembodiments, the Active Agent is administered in a single-dosed amountof about 200 μg to about 2000 μg.

In certain embodiments within the various aspects and embodiments of thepresent invention, the Active Agent is administered by infusion. In oneembodiment, the infusion is performed at a rate of about 3 μg (μgm orμg)/minute to about 60 μg/min; about 6 μg/minute to about 30 μg/minute;about 12/minute to about 15 μg/minute; about 7 μg/minute to about 18μg/minute; about 9 μg/minute; about 13 μg/minute; and about 16μg/minute.

In yet another embodiment, the patient is administered intravenously for15 minutes at about 40 μg/min and then about 45 minutes at about 13μg/min. In yet another embodiment, in accordance with the inventionmethods, the patients are those who have been admitted to an emergencyroom. In still other embodiments, the patient may be treated in thevicinity of where the acute exacerbation of asthma occurred, or whilebeing transported to a hospital (e.g., in an emergency rescue vehicle orambulance).

In yet another embodiment, in accordance with the invention methods, thepatient is administered an initial amount of the Active Agent in therange of about 3 μg/kg patient (or about 200 μg per patient) to about 60μg/kg patient (or about 4 mg per patient). The Active Agent may beadministered over a period of about 1 minute to up to about 4 hours.

In certain embodiments within the various aspects and embodiments of thepresent invention, the Active Agent is administered for a period of timeup to about 3 hours (h), up to about 2 h, up to about 1 h, up to about45 min, up to about 30 min, and up to about 15 min. The Active Agent maybe administered at various rates of administration, for various periodsof time.

In some embodiments, the composition is administered as a formulationsuitable for parenteral routes of administration, such as intravenousinjection or infusion, intramuscular, percutaneous, and subcutaneousadministration. For parenteral application, particularly suitable aresolutions, preferably oily or aqueous solutions, as well as suspensions,emulsions, or implants, including suppositories.

In a related embodiment, the intravenous formulation comprisesapproximately 0.20 mg to about 20 mg; or alternatively about 0.20 mg toabout 10 mg; or alternatively about 0.20 mg to about 5 mg; oralternatively about 0.20 mg to about 3 mg; or alternatively about 0.20mg to about 2 mg; or alternatively about 0.20 mg to about 1 mg; of thecompound of the invention in an aqueous delivery system. The aqueousdelivery system may comprise about 0.02% to about 0.5% (w/v) of anacetate, phosphate, or citrate buffer. In another aspect, theformulation has a pH of about 3.0 to about 7.0. In a related aspect, theconcentration of the compound in the intravenous formulation falls inthe range of about 0.15 μmol/mL to about 0.25 μmol/mL.

In some embodiments, the subject is administered an amount of thecompound of the invention in the range of about 3 μg/kg patient (orabout 200 μg per patient) to about 60 μg/kg patient (or about 4 mg perpatient). The dosage may be administered intravenously as a single bolusinjection to the subject, or as single bolus injection followed by aconstant infusion for up to 24, 36, 48, or 72 hours, or as a constantinfusion for up to 24, 36, 48, or 72 hours. The dosage may beadministered subcutaneously or intravenously at intervals not less than4 hours and for up to 24, 36, 48, or 72 hours. In some embodiments, thesubject is administered intravenously for 15 minutes at about 40 μg/minand then about 45 minutes at about 13 μg/min.

In some embodiments, the intravenous formulation is reconstituted from afreeze-dried drug product comprising the compound of the invention. Inanother embodiment, the freeze-dried drug product further comprisescarbohydrate and/or polyhydric alcohols. The carbohydrate may bemannose, ribose, trehalose, maltose, inositol, lactose, or the like. Thepolyhydric alcohols may be sorbitol, mannitol, or the like. Thepharmaceutical composition comprising the Active Agent can also beadministered using a nebulizer (i.e., inhaled) or administeredenterally, such as orally.

In one embodiment, the liquid formulation comprises the Active Agent inan amount of about 3 μg/mL to about 60 μg/mL, about 6 μg/mL to about 30μg/mL, and about 12 μg/mL to about 30 μg/mL, and about 15 μg/mL to about20 μg/mL. In another embodiment, the liquid formulation furthercomprises dextrose.

EXAMPLES

The following examples are provided to illustrate certain aspects of thepresent invention and to aid those of skill in the art in practicing theinvention. These examples are not intended to limit the scope of theinvention. In particular, while the administration of MN-221 isexemplified below, it is anticipated that similar results are obtainedusing any one of the other members comprising “Active Agent.”

Example 1 Safety and Efficacy of In Vivo Administration of MN-221

In preclinical studies, intravenously administered MN-221 (0.04 to 0.4mg/kg) at the peak of ragweed-induced bronchoconstriction demonstrated astatistically significant, and near maximal reversal ofbronchoconstriction in ragweed sensitized dogs between 0.75 and 6.7 min(p<0.001 up to 4.5 min and p<0.01 up to 6.7 min) after dosing.

In a separate study with telemetered dogs at the Lovelace RespiratoryResearch Institute, the effect of i.v. MN-221 administration in additionto nebulized albuterol was performed to assess cardiovascular changesand safety of the combination therapy. Albuterol was administered byinhalation at 5 or 10 ug/kg and MN-221 was intravenously administeredover 15 min at 0.3, 3, or 30 ug/kg. As expected with beta-agonists andas shown in other model systems, both albuterol and MN-221, alone,increased heart rate to a modest level depending on dose. No adversechanges in MAP or QTc were observed with either agent at any dose. Mostimportantly and most pertinent to the discovery described herein, whenclinically-relevant doses of MN-221 were added on top ofclinically-relevant albuterol doses, there was no additional increase inheart rate. See, FIG. 3. And other cardiovascular parameters (MAP, QTc)were not adversely changed with combination therapy.

Example 2 Administration of MN-221 for the Treatment of AEA

MN-221 was tested at escalating doses of 240 μg to 1,080 μg in patientswith AEA treated in emergency departments (EDs). The study included 29(13 treated with SOC only and 16 treated with MN-221 in combination withSOC) patients with severe AEA. All patients were administered SOCtreatment as follows: supplemental oxygen given to maintain oxygensaturation measured by pulse oximetry of ≧90%; two doses of inhaledbeta2-agonist (in this study, albuterol 5 mg) via nebulizer givenapproximately every 20 minutes; simultaneously with two doses of aninhaled anti-cholinergic agent (in this study, ipratropium 0.5 mg) vianebulizer given approximately every 20 minutes; one dose ofcorticosteroid given orally (in this study, prednisone 60 mg) orintravenously (in this study, methylprednisolone 125 mg), andintravenous magnesium sulfate (2 gm, diluted with 50-100 mL normalsaline) and given over 10 minutes to patients with an FEV₁ ≦25% ofpredicted upon ED presentation treatment.

MN-221 was administered at the following doses: 16 μg/min for 15 minutes(total of 240 μg); 30 μg/min for 15 minutes (total of 450 μg); 16 μg/minfor 15 minutes; 8 μg/min for 105 minutes (total of 1,080 μg). Alyophilized unit dose for of MN-221, containing 2 mg MN-221 and lactosein a 10 mL vial was employed in the administration. Vials containing 2mg (2000 μg) of MN-221 and vials containing placebo were reconstitutedas follows. 4 mL of 5% dextrose in water was added to each 10 mL vialcontaining MN-221 to make 500 μg/mL stock solution (2000 μg/4 mL=500μg/mL). 2 mL (1,000 μg) of stock solution was added to 123 mL 5%dextrose in water to make the total volume of 125 mL (123 mL+2 mL=125mL). Final MN-221 solution equal to 1,000 μg/125 mL or 8 μg/mL wasprepared this way.

Patients were administered SOC treatment (inhaled albuterol, 2.5 mg vianebulizer up to every 20 minutes) and ipratropium (0.5 mg via nebulizerup to every 20 minutes) in addition to treatment with MN-221 or placebo.

The hospital admission rate was lower in the all MN-221 group (4/16patients, 25%) compared with the placebo group (7/13 patients, 54%). Theresults demonstrated more than 50% reduction in hospitalization rateamong patients treated with MN-221. Improvement in forced expiratoryvolume in 1 second (FEV₁) values generally appeared to be greater forpatients receiving MN-221 in addition to SOC treatment. No safetyconcerns with adding MN-221 to standardized care were identifiedfollowing review of electrocardiogram (ECG), laboratory, and adverseexperience data. This example demonstrates the usefulness ofadministering MN-221 in accordance with the various aspects andembodiments of the present invention in the treatment of AEA and statusasthmaticus.

Example 3 Demonstration of Safety and Efficacy of MN-221 Administrationto AEA Patients

A randomized, double-blind, placebo-controlled Phase II clinical trialis performed for demonstrating the efficacy and safety of administeringMN-221 in accordance with the various aspects and embodiments of themethods of the present invention. A patient is administered thefollowing initial SOC treatment regimen (consistent with the NationalAsthma Education and Prevention Program and the Global Initiative forAsthma (GINA) guidelines). The SOC includes the following: supplementaloxygen given to maintain oxygen saturation as measured by pulse oximetryof ≧90% as needed; albuterol: 10 mg of albuterol via nebulizer prior tothe qualifying spirometry evaluation; simultaneously with ipratropium:1.0 mg of ipratropium via nebulizer prior to the qualifying spirometryevaluation (if a nebulizer is not used, albuterol and ipratropium may beadministered using an MDI with spacer as follows; albuterol: 16 puffs ofalbuterol (90 μg/puff) via MDI with spacer prior to the qualifyingspirometry evaluation, simultaneously with ipratropium: 16 puffs ofipratropium (18 μg/puff) via MDI with spacer prior to the qualifyingspirometry evaluation); the patient is assessed for response to thattreatment; one dose of at least 50 mg of a corticosteroid given eitherorally (prednisone) or intravenously (methylprednisolone) or theequivalent dose of another corticosteroid; and treatment with magnesiumsulfate, e.g., patients with an FEV₁ ≦25% of predicted, benefited fromreceiving 2 gm of intravenous magnesium sulfate therapy.

In a particular study patients receive during a screening period thefollowing standard treatment (in addition to the albuterol andipratropium doses received during a pre-screening period): supplementaloxygen given to maintain oxygen saturation as measured by pulse oximetryof ≧90% as needed; albuterol: a dose of at least 2.5 mg but not morethan 7.5 mg of albuterol via nebulizer to be given during the screeningperiod, simultaneously with ipratropium: a dose of 0.5 mg of ipratropiumvia nebulizer to be given during the screening period. If a nebulizer isnot used, albuterol: a dose of at least 6 puffs but not more than 18puffs (90 μg/puff) via MDI with spacer to be given during the screeningperiod, simultaneously with ipratropium: a dose of 8 puffs (18 μg/puff)via MDI with spacer to be given during the screening period. If thepatient's FEV₁ is less than or equal to 50 percent of predicted and thepatient meets all other study entry criteria, the patient is randomizedto receive either MN-221 or placebo. Patients enrolled in the studyreceive an intravenous 1-hour infusion of MN-221 study drug or placebo.Two (2) mg Lyophilized unit dose forms of MN-221 are used as dugproduct. After reconstituting with D5W, an aqueous formulation of 13.3μg/mL MN-221 is administered to the patients. Patients administeredMN-221, receive a total dose of 1200 μg (40 μg/min for 15 min [600μg]+13.3 μg/min for 45 min [600 μg]); i.e., patients receive 1200 μgover a period of 1 h.

Patients enrolled in the study are administered SOC, as needed, incombination with MN-221 while being administered an intravenous infusionof MN-221, or with placebo. The following SOC is administered.Supplemental oxygen is optionally administered to maintain oxygensaturation as measured by pulse oximetry of ≧90% as needed; albuterol: adose of at least (2.5 mg) but not more than 7.5 mg of albuterol vianebulizer to be administered hourly during the treatment period;ipratropium: a dose of (0.5 mg) of ipratropium via nebulizer isoptionally administered hourly during the treatment period. Ifnebulizers are not used, SOC may be administered by MDI. The primaryefficacy endpoint is improvement in FEV₁.

Example 4 MN-221 Formulation for Intravenous Administration

MN-221 (2 mg) is formulated as an aseptically processed lyophilizedproduct for injection, as tabulated below.

TABLE 3 Ingredient Function Amount in mg/vial MN-221 drug substanceActive 2 ingredient Polyhydric Alcohol, USP/EP Filler 200 Water forInjection, USP/EP Solvent for Removed during production lyophilizationNitrogen, NF To fill vial QS headspaceThe formulation is administered intravenously after reconstitution with5 mL of Dextrose Injection 5% or other parenterally acceptable solution.

Example 5 Administration of MN-221 as a First Line Combination Therapy

Patients showing symptoms of exacerbation of asthma, in an emergencydepartment (ED) or in a prehospital setting, are treated byadministration of MN-221, as described in Example 5, and additionally anSOC is administered or applied in combination. As part of the SOC,albuterol (about 10 mg) is administered, without or with ipratropium(about 1 mg), via nebulizers. If a nebulizer is not used, albuterol andipatroprium are administered using an MDI with spacer as follows. Foralbuterol, about 16 puffs of albuterol (90 μg/puff, and for ipratropium,about 16 puffs of ipratropium (18 μg/puff) are administered.Additionally, some patients are also administered a dose of about 50 mgof a corticosteroid given either orally (prednisone) or intravenously(methylprednisolone). Additionally, some patients are also administeredabout 2 gm of intravenous magnesium sulfate. Supplemental oxygen is alsogiven to maintain oxygen saturation as measured by pulse oximetry of≧90%.

While certain aspects and embodiments of the present technology havebeen illustrated and described, it will be understood that changes andmodifications can be made therein in accordance with ordinary skill inthe art without departing from the present technology in its broaderaspects as defined in the following claims.

1. A method of improving one or more clinical outcomes of an individualexperiencing an acute respiratory attack selected from the groupconsisting of acute reversible bronchospasm, severe acute bronchospasmand acute exacerbation of asthma, comprising administering to anindividual suffering from an acute respiratory attack an effectiveamount of bedoradrine or a pharmaceutically acceptable salt thereof incombination with a standard of care (SOC) treatment regimen.
 2. Themethod of claim 1 in which the bedoradrine or a pharmaceuticallyacceptable salt thereof is administered after administration of the SOCtreatment regimen.
 3. The method of claim 1 in which the bedoradrine ora pharmaceutically acceptable salt thereof is administeredcontemporaneously with the SOC treatment regimen.
 4. The method of claim1 in which the bedoradrine or a pharmaceutically acceptable salt thereofis administered before administration of the SOC treatment regimen. 5.The method of claim 1 in which the SOC treatment regimen comprisesadministration of one or more β-agonist bronchodilators, one or moreanti-cholinergic drugs, one or more corticosteroids, or combinationsthereof.
 6. The method of claim 1 in which the SOC treatment regimenincludes the administration of magnesium.
 7. The method of claim 5 inwhich the one or more β-agonist bronchodilators, or one or moreanti-cholinergic drugs are administered by inhalation, injection, orintravenous infusion.
 8. The method of claim 5 in which the one or moreβ-agonist bronchodilators are selected from albuterol, bitolterol,levalbuterol, pirbuterol, epinephrine, terbutaline, formoterol andsalmeterol.
 9. The method of claim 5 in which the one or moreanti-cholinergic drugs are selected from ipratropium and tiotropium. 10.The method of claim 5 in which the one or more corticosteroids areselected from prednisone, methylprednisolone and prednisolone.
 11. Themethod of claim 1 in which the bedoradrine or a pharmaceuticallyacceptable salt thereof is administered intravenously.
 12. The method ofclaim 1 in which the bedoradrine or a pharmaceutically acceptable saltthereof is administered orally.
 13. The method of claim 1 in which thebedoradrine or a pharmaceutically acceptable salt thereof isadministered by inhalation.
 14. The method of claim 1 in which theamount of bedoradrine or a pharmaceutically acceptable salt thereofadministered to the individual falls in the range of 100 to 5,000 μg.15. The method of claim 14 in which about 500 to about 1,500 μg ofbedoradrine or a pharmaceutically acceptable salt thereof isadministered intravenously over a period of about 5 to about 120minutes.
 16. The method of claim 1 in which the patient has beenadmitted to an emergency room.
 17. The method of claim 1 in which theone or more clinical outcomes improved is selected from an increase inFEV₁, a reduction in likelihood of hospitalization, an improvement indyspnea scores, a reduction in incidence of intubation, a reduction inlength of stay in an intensive care unit and an improvement inself-ambulation unaccompanied by respiratory distress.
 18. The method ofclaim 17 in which FEV₁ improves by 5% or more, 10% or more, or 15% ormore.
 19. The method of claim 17 in which the likelihood ofhospitalization of the individual receiving the combination treatment isreduced compared with an individual receiving only the SOC treatmentregimen.
 20. The method of claim 19 in which the likelihood ofhospitalization of the individual receiving the combination treatment isreduced to about 25% or less, about 20% or less, or about 15% or less.21. The method of claim 1 in which the individual is not responsive toan inhaled β-agonist bronchodilator.
 22. The method of claim 21 in whichthe inhaled β-agonist bronchodilator is albuterol.
 23. The method ofclaim 1 in which the individual experiences improvement from the acuterespiratory attack for about 1 hour or more, about 2 hours or more,about 3 hours or more, about 4 hours or more, about 5 hours or more,about 6 hours or more, or about 8 hours or more after the combinationtreatment.
 24. The method of claim 1 in which the individual experiencesimprovement in FEV₁ (L), FEV₁ (% predicted), PEFR, arterial blood oxygensaturation, respiratory rate, or combinations thereof after thecombination treatment, unaccompanied by one or more clinicallyobservable adverse events.
 25. The method of claim 24 in which the oneor more clinically observable adverse events is selected from anincreased heart rate, an increased blood glucose, tremor, headache,palpitations and a jittery feeling.
 26. A method of alleviating one ormore negative effects of an acute respiratory attack selected from thegroup consisting of acute reversible bronchospasm, severe acutebronchospasm and acute exacerbation of asthma, comprising administeringto a patient, who has been diagnosed as suffering from either acutereversible bronchospasm, severe acute bronchospasm, or acuteexacerbation of asthma, an effective amount of bedoradrine or apharmaceutically acceptable salt thereof.
 27. The method of claim 26 inwhich the patient suffers from acute exacerbation of asthma.
 28. Themethod of claim 27 in which the patient fails to respond to the SOCtreatment regimen.
 29. The method of claim 27 in which the patientexperiences improved FEV₁ relative to the patient's pre-treatment FEV₁and the improved FEV₁ persists on average for at least about 6 hours ata level that is about 50% or more of a peak effect.
 30. The method ofclaim 27 in which the daily amount of bedoradrine or a pharmaceuticallyacceptable salt thereof administered to the patient falls in the rangeof about 300 to 1500 μg.
 31. The method of claim 1 or 26 in which theindividual or patient belongs to an exacerbation-prone subset ofasthmatics.